tbuckley/cabot-search huggingface dataset:
Acalabrutinib ± obinutuzumab versus obinutuzumab + chlorambucil in treatment-naïve chronic lymphocytic leukemia: Five-year follow-up of ELEVATE-TN.
Authors: Jeff Porter Sharman, Miklos Egyed, Wojciech Jurczak, Alan P. Skarbnik, Manali K. Kamdar, Talha Munir, Laura Fogliatto, Yair Herishanu, Versha Banerji, George Follows, Patricia Walker, Karin Karlsson, Paolo Ghia, Ann Janssens, Emmanuelle Ferrant, Veerendra Munugalavadla, Ting Yu, Min Hui Wang, Jennifer Ann Woyach
Journal: Journal of Clinical Oncology (2022)

7539 Background: For ELEVATE-TN (NCT02475681), we previously reported superior efficacy of acalabrutinib (A) ± obinutuzumab (O) vs O + chlorambucil (Clb) in patients (pts) with treatment-naive (TN) chronic lymphocytic leukemia (CLL) at 28.3 and 46.9 months (mo) median follow-up. Now, we report results from a 5-y update. Methods: Pts were randomized to A+O, A, or O+Clb. Pts who progressed on O+Clb could cross over to A monotherapy. Investigator-assessed (INV) progression-free survival (PFS), INV overall response rate (ORR), overall survival (OS), and safety were evaluated. Results: A total of 535 pts (A+O, n=179; A, n=179; O+Clb, n=177) had a median age of 70 y. At a median follow-up of 58.2 mo (range, 0.0–72.0; data cutoff Oct 1, 2021), median PFS was not reached (NR) (hazard ratio [HR]: 0.11) for A+O and A (HR: 0.21) vs 27.8 mo for O+Clb (both P&lt;0.0001). Estimated 60-mo PFS rates were 84% (A+O), 72% (A), and 21% (O+Clb). Median OS was NR in any treatment arm, and significantly longer in the A+O vs O+Clb arms (HR: 0.55; P=0.0474); estimated 60-mo OS rates were 90% (A+O), 84% (A), and 82% (O+Clb). ORR was significantly higher with A+O (96%; 95% CI 92–98) and A (90%; 85–94) vs O+Clb (83%; 77–88; P&lt;0.0001 [A+O], P=0.0499 [A]). Complete response (CR)/CR with incomplete hematologic recovery (CRi) rates were higher with A+O (29%/3%) vs O+Clb (13%/1%); 13%/1% had CR/CRi with A; CR increased since the interim analysis (previously 21% [A+O] and 7% [A]). Adverse events (AEs) and treatment exposure are shown in the Table. Treatment is ongoing in 65% (A+O) and 60% (A) of pts; the most common reasons for treatment discontinuation were AEs (17% [A+O], 16% [A], 14% [O+Clb]) and progressive disease (6%, 10%, 2%, respectively). Crossover from O+Clb to A occurred in 72 (41%) patients; 25% of these pts discontinued A (10% due to AEs and 11% due to progressive disease). Conclusions: After a 5-y follow-up, efficacy and safety of A+O and A monotherapy were maintained, with significantly longer OS in the A+O arm compared with O+Clb. Clinical trial information: NCT02475681. [Table: see text]
Primary focal cryotherapy for non-metastatic prostate cancer: Update from the UK ICE registry
Authors: D.T. Reddy, M. Peters, T. Shah, M. Van Son, M. Bertoncelli Tanaka, P. Huber, D. Lomas, A. Rakauskas, S. Miah, D. Eldred-Evans, F. Hosking-Jervis, R. Engle, T. Dudderidge, S. Mccracken, D. Greene, R. Nigam, N. Mccartan, M. Valerio, C. Orczyk, J. Virdi, M. Arya, H. Ahmed
Journal: European Urology (2022)
Modulation of radiation biomarkers in a randomized phase II study of <sup>131</sup>I-MIBG with or without radiation sensitizers for relapsed or refractory neuroblastoma: A report from the NANT Consortium.
Authors: Kevin M. Campbell, Susan G. Groshen, Araz Marachelian, Myriam Armant, Sharmistha Pal, Daphne A. Haas-Kogan, Angela Clare Evans, Matthew A. Coleman, Julie R. Park, Meaghan Granger, Katherine K. Matthay, Steven G. DuBois
Journal: Journal of Clinical Oncology (2022)

10026 Background: 131 I-metaiodobenzylguanidine ( 131 I-MIBG) has demonstrated efficacy as a single agent for patients with neuroblastoma. Recent trials have focused on 131 I-MIBG combination strategies, though little is known about the impact of combination agents on markers of radiation exposure. Methods: NANT11-01 (NCT02035137) was a multicenter, open label, randomized phase II clinical trial that evaluated 131 I-MIBG therapy alone (Arm A) or in combination with vincristine/irinotecan (Arm B) or vorinostat (Arm C) for patients with resistant/relapsed neuroblastoma. We collected blood samples at baseline, 72 hours, 96 hours, and 15 days after 131 I-MIBG infusion and determined levels of plasma FLT3 ligand, serum amylase, and gene expression for selected RNA transcripts (apoptosis, DNA damage response and cell cycle related). We evaluated marker association with treatment arm, clinical response using NANT response criteria, toxicity, and whole-body radiation dose. Results: The cohort included 99 patients who had at least one biomarker available for analysis (32 Arm A; 35 Arm B; 32 Arm C). We observed both positive and negative significant modulation in most biomarkers between baseline, 72 hours, and 96 hours following 131 I-MIBG. Patients in Arm C had the lowest degree of modulation in FLT3 ligand. Elevated baseline levels of FLT3 ligand were significantly associated with improved Curie response but not overall response. Lower baseline BCL2 levels were associated with higher overall and Curie response. Patients with increased FLT3 ligand at 96 hours after 131 I-MIBG therapy were significantly more likely to have grade 4 thrombocytopenia.Peripheral blood gene expression of the BCL2 family of apoptotic markers (BCL2/L1 and BAX) was significantly associated with grade 4 hematological toxicity. Whole-body radiation dose and PRKDC fold change at 72 hours were significantly correlated. No other individual biomarkers were correlated with whole body radiation dose at 72 or 96 hours post 131 I-MIBG. Conclusions: Peripheral blood biomarkers relevant to radiation exposure demonstrate significant modulation over time after 131 I-MIBG treatment. Biomarkers related to hematopoietic damage and apoptosis were associated with hematological toxicity. Patients treated with vorinostat and 31 I-MIBG had differential modulation of FLT3-ligand Further use of these biomarkers may improve our ability to care for patients treated with 131 I-MIBG.
DSP-0390, an oral emopamil binding protein (EBP) inhibitor, in patients with recurrent high-grade glioma: A first-in-human, phase 1 study.
Authors: David A. Reardon, Yoshitaka Narita, Yoshiki Arakawa, Samuel A. Goldlust, George Ansstas, Jian Mei, Edward Dow, Masataka Seki, Yudai Furuta, Gregory Song, Howard Colman
Journal: Journal of Clinical Oncology (2022)

TPS2077 Background: The brain’s cells are fully dependent on their own de novo biosynthesis of cholesterol as the blood-brain barrier prevents its uptake from the circulation. In normal glial cells, proper regulation of cholesterol synthesis depends on its cell density and is turned off when the cell density exceeds a certain level. On the other hand, gliomas maintain high levels of cholesterol synthesis to support abnormal growth under any condition. Upregulation of cholesterol synthesis genes is associated with decreased survival in patients with glioblastoma (GBM). Therefore, gliomas are potentially sensitive to cholesterol synthesis inhibition. DSP-0390, an investigational small molecule, is an inhibitor of EBP, an enzyme in one of the last and crucial steps of cholesterol biosynthesis. By inhibiting de novo cholesterol synthesis, cytotoxicity can be induced more selectively against hyperproliferative GBM cells. DSP-0390 has shown significant antitumor activity in orthotopic xenograft models of human GBM (data on file). Methods: DSP-0390 will be evaluated in a phase 1 study in patients with recurrent, high-grade glioma (NCT05023551). Key eligibility criteria: age ≥18 years; Karnofsky Performance Status score ≥70%; and adequate renal, hepatic, and hematologic function. Patients must not have multifocal disease, leptomeningeal metastasis or extracranial metastasis, abnormal electrocardiograms, or significant cardiovascular disease. In Dose Escalation, 21–30 patients with World Health Organization (WHO) grade III or IV malignant glioma who progressed after ≥1 prior therapy will be enrolled. Dose level enrollment will be guided by a Bayesian Logistic Regression Model until identification of the maximum tolerated dose or recommended dose for expansion. Dose Expansion for clinical activity will enroll approximately 20–40 patients with WHO grade IV GBM who progressed after primary therapy and have measurable disease. Patients will receive oral DSP-0390 once daily. Study endpoints include safety (treatment-emergent adverse events [AEs], serious AEs, and dose-limiting toxicities), efficacy (6-month progression-free survival [PFS], objective response, PFS, duration of response, and 12-month overall survival), pharmacokinetics (PK), and pharmacodynamic biomarkers. This study is currently recruiting in the United States and Japan. Clinical trial information: NCT05023551.
Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells
Authors: Mareike Berlak, Elizabeth Tucker, Mathurin Dorel, Annika Winkler, Aleixandria McGearey, Elias Rodriguez-Fos, Barbara Martins da Costa, Karen Barker, Elicia Fyle, Elizabeth Calton, Selma Eising, Kim Ober, Deborah Hughes, Eleni Koutroumanidou, Paul Carter, Reda Stankunaite, Paula Proszek, Neha Jain, Carolina Rosswog, Heathcliff Dorado-Garcia, Jan Jasper Molenaar, Mike Hubank, Giuseppe Barone, John Anderson, Peter Lang, Hedwig Elisabeth Deubzer, Annette Künkele, Matthias Fischer, Angelika Eggert, Charlotte Kloft, Anton George Henssen, Michael Boettcher, Falk Hertwig, Nils Blüthgen, Louis Chesler, Johannes Hubertus Schulte
Journal: Molecular Cancer (2022)

Abstract Background Development of resistance to targeted therapies has tempered initial optimism that precision oncology would improve poor outcomes for cancer patients. Resistance mechanisms, however, can also confer new resistance-specific vulnerabilities, termed collateral sensitivities. Here we investigated anaplastic lymphoma kinase (ALK) inhibitor resistance in neuroblastoma, a childhood cancer frequently affected by activating ALK alterations. Methods Genome-wide forward genetic CRISPR-Cas9 based screens were performed to identify genes associated with ALK inhibitor resistance in neuroblastoma cell lines. Furthermore, the neuroblastoma cell line NBLW-R was rendered resistant by continuous exposure to ALK inhibitors. Genes identified to be associated with ALK inhibitor resistance were further investigated by generating suitable cell line models. In addition, tumor and liquid biopsy samples of four patients with ALK -mutated neuroblastomas before ALK inhibitor treatment and during tumor progression under treatment were genomically profiled. Results Both genome-wide CRISPR-Cas9-based screens and preclinical spontaneous ALKi resistance models identified NF1 loss and activating NRAS Q61K mutations to confer resistance to chemically diverse ALKi. Moreover, human neuroblastomas recurrently developed de novo loss of NF1 and activating RAS mutations after ALKi treatment, leading to therapy resistance. Pathway-specific perturbations confirmed that NF1 loss and activating RAS mutations lead to RAS-MAPK signaling even in the presence of ALKi. Intriguingly, NF1 loss rendered neuroblastoma cells hypersensitive to MEK inhibition. Conclusions Our results provide a clinically relevant mechanistic model of ALKi resistance in neuroblastoma and highlight new clinically actionable collateral sensitivities in resistant cells.
Ten-year outcome of a prospective randomised trial comparing laparoscopic versus robot-assisted radical prostatectomy
Authors: E. Checcucci, E. Alladio, S. De Cillis, S. Granato, D. Amparore, A. Piana, F. Piramide, G. Volpi, M. Sica, P. Verri, S. Piscitello, B. Carbonaro, J. Meziere, D. Zamengo, M. Della Corte, A. Pecoraro, G. Cattaneo, M. Di Dio, M. Manfredi, F. Porpiglia
Journal: European Urology (2022)
MEDB-42. Germline<i>Elp1</i> deficiency promotes genomic instability and survival of granule neuron progenitors primed for SHH medulloblastoma pathogenesis
Authors: Jesus Garcia-Lopez *, Shiekh Tanveer Ahmad *, Yiran Li *, Brian Gudenas, Marija Kojic, Friedrik Manz, Barbara Jonchere, Anand Mayasundari, Aaron Pitre, Jennifer Hadley, Leena Paul, Melissa Batts, Brandon Bianski, Christopher Tinkle, Brent Orr, Zoran Rankovic, Giles Robinson, Martine Roussel, Brandon Wainwright, Lena Kutscher, Hong Lin #, Paul Northcott #
Journal: Neuro-Oncology (2022)

Abstract Germline loss-of-function (LOF) mutations in Elongator complex protein 1 (ELP1) are found in 15-20% of childhood SHH medulloblastoma (MB) and are exceedingly rare in non-SHH-MB or other cancers. ELP1 germline carriers that develop SHH-MB harbor frequent somatic PTCH1 mutations and universally sustain loss-of-heterozygosity of the remaining ELP1 allele through chromosome 9q deletion. ELP1 functions as a scaffolding subunit of the Elongator complex that is required for posttranscriptional modification of tRNAs and maintenance of efficient translational elongation and protein homeostasis. However, the molecular, biochemical, and cellular mechanisms by which ELP1/Elongator LOF contribute to SHH-MB tumorigenesis remain largely unknown. Herein, we report that mice harboring germline Elp1 monoallelic loss (i.e., Elp1+/-) exhibit hallmark features of malignant predisposition in developing cerebellar granule neuron progenitors (GNPs), the lineage-of-origin for SHH-MB. Elp1+/- GNPs are characterized by increased replication stress-induced DNA damage, upregulation of the homologous recombination repair pathway, aberrant cell cycle, and attenuation of p53-dependent apoptosis. CRISPR/Cas9-mediated Elp1 and Ptch1 gene targeting in mouse GNPs reproduces highly penetrant SHH-MB tumors recapitulating the molecular and phenotypic features of patient tumors. Reactivation of the p53 pathway through MDM2 and PAK4 inhibitors promotes selective cell death in patient-derived xenograft tumors (PDX) harboring deleterious ELP1 mutations. Together, our findings reveal that germline Elp1 deficiency heightens genomic instability and survival in GNPs, providing a mechanistic model for the subgroup-restricted pattern of predisposition and malignancy associated with pathogenic ELP1 germline carriers. These results provide rationale for further preclinical studies evaluating drugs that overcome p53 pathway inhibition in ELP1-associated SHH-MB and a renewed outlook for improving treatment options for affected children and their families.*, # Contributed equally
MEDB-59. A draft atlas of medulloblastoma cellular evolution under therapy
Authors: Lin Wang, Jangham Jung, Husam Babikir, Karin Shamardani, Noriyuki Kasahara, Sabine Müller, Aaron Diaz
Journal: Neuro-Oncology (2022)

Abstract How standard care shapes the cellular composition of recurrent medulloblastoma (MB), if therapy selects for specific tumor or immune cell types, is unknown. We report the pilot phase of our ongoing effort to profile human longitudinal MB specimens via single-cell transcriptomics and epigenetics. We profiled 11 diagnostic and eight recurrent specimens from 19 subjects via single-nucleus RNA sequencing (snRNA-seq), and four subjects via single-nucleus assay for transposase-accessible chromatin. Specimens from select subjects were also profiled to assess genome-wide enhancer activity via single-nucleus cleavage-under-targets and tagmentation. We found an upregulation of the DNA-damage response, RNA translation, WNT and NOTCH signaling in recurrent specimens. The percentages of stem-like cells increased by over two-fold at recurrence. We found that microglia and oligodendrocyte-lineage cells were the most abundant non-malignant tumor-associated cell types, representing 2%-10% of cells profiled. Microglia abundances were relatively stable across molecular subtypes, and when comparing primary to recurrent tumors. There was a moderate, but statistically significant, increase in oligodendrocyte abundance in SSH and WNT tumors, compared to Group 3/4 tumors. We compared gene expression in tumor cells with public snRNA-seq from developing human cerebella (PCW 9-21). Combined Group-3/4 cell analysis supports a common lineage hierarchy, with an enrichment for unipolar brush-cell and Purkinje-cell phenotypes found in Group-4 tumors. All Group-3/4 cases contained cycling cells expressing markers of PAX2+ interneuron progenitors, most cycling cells had this phenotype. All specimens contained populations of non-cycling granule-cell progenitor-like cells. We performed single-cell co-expression receptor/ligand analysis to infer paracrine signaling between tumor and non-malignant cell types. This identified both tumor cells and microglia as sources of growth factors, pro-inflammatory cytokines, and pro-apoptotic ligands. Non-malignant oligodendrocyte-lineage cells uniquely expressed IL6-family cytokines, pleiotrophin, and class-III semaphorins. These studies shed light on the cellular heterogeneity of MB and the effect of standard therapy in shaping composition at recurrence.
Interception versus prevention in cancer screening in a Medicare population: Results from the CRC-MAPS model.
Authors: Girish Putcha, Lauren N Carroll, Tarun Chandra, Andrew Piscitello
Journal: Journal of Clinical Oncology (2022)

10546 Background: This study examines the impact of detecting cancer (interception) versus adenomas and cancer (prevention + interception) on clinical outcomes in a screen-naive Medicare cohort for a hypothetical colorectal cancer (CRC) screening test or a multicancer early detection (MCED) test that includes CRC. Methods: CRC-MAPS, a validated microsimulation model of the adenoma-carcinoma pathway that reproduced incidence reduction (IR) and mortality reduction (MR) consistent with CISNET models and a randomized controlled trial, was used to simulate perfect adherence to a hypothetical annual screening test among previously unscreened individuals free of diagnosed CRC. Four scenarios were examined: two cancer interception and two cancer prevention + interception. Individuals were screened from age 65 to 75. CRC IR and MR outcomes compared to no screening were aggregated from age 65 until death. Threshold analysis (#5) identified the ≥10mm adenoma sensitivity needed for a base-case cancer interception test (#1) to yield CRC MR equivalent to a near-perfect cancer interception test (#2). Results: The base-case interception scenario (#1) resulted in 5.6% CRC IR and 21.7% MR compared to 5.2% CRC IR and 25.9% MR for the near-perfect interception scenario (#2). The threshold analysis demonstrates that when the base-case interception scenario's ≥10mm adenoma sensitivity is increased from 1% to just 2.43% (#5), the resulting MR is equivalent to a near-perfect interception test. Accordingly, the cancer prevention + interception scenarios (#3, #4) resulted in CRC IR and MR outcomes 9.7-12.9x and 2.5-3.4x (respectively) as favorable as either cancer interception scenario due to adenoma detection. Conclusions: This analysis highlights that even small improvements in the detection of precancerous lesions for certain cancers (e.g., adenomas for CRC), which enable cancer prevention, can yield clinical benefits that meaningfully exceed those from tests that primarily detect cancer. Future studies will explore both benefits and burdens of different screening tests. Moreover, this approach will be applied to better understand the clinical utility of MCED tests. [Table: see text]
Clinical outcomes associated with SARS-CoV-2 Omicron (B.1.1.529) variant and BA.1/BA.1.1 or BA.2 subvariant infection in Southern California
Authors: Joseph A. Lewnard, Vennis X. Hong, Manish M. Patel, Rebecca Kahn, Marc Lipsitch, Sara Y. Tartof
Journal: Nature Medicine (2022)
Validation of a 22-gene Epithelial-Mesenchymal Transition (EMT) prognostic signature in clear cell renal cell carcinoma
Authors: B.H. Cotta, S. Nallandhighal, J. Stangl-Kremser, T. Pham, J.J. Tosoian, K. Marchetti, J. Berends, M. Maruf, S.A. Tomlins, T.M. Morgan, G.S. Palapattu, E. Abdulfatah, A.M. Udager, S.S Salami
Journal: European Urology (2022)
Patient-reported outcomes from the phase 3 HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma.
Authors: Bruno Sangro, Peter R Galle, Robin Kate Kelley, Chaiyut Charoentum, Enrico N De Toni, Yuriy Ostapenko, Jeong Heo, Ann-Lii Cheng, Arndt Vogel, Michelle Marcovitz, Jayne Abraham, Nikunj Patel, Alejandra Negro, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2022)

4074 Background: In the Phase 3 HIMALAYA study (NCT03298451) of patients (pts) receiving first-line treatment for unresectable hepatocellular carcinoma (uHCC), a single priming dose of tremelimumab (T; anti-CTLA-4) plus durvalumab (D; anti-PD-L1) in the STRIDE regimen significantly improved overall survival (OS) vs sorafenib (S), and D monotherapy was noninferior to S for OS (Abou-Alfa et al. J Clin Oncol 2022;40[suppl 4]. Abs 379). Methods: A pre-planned secondary objective of HIMALAYA was to assess pt-reported outcomes (PROs) in pts receiving STRIDE (T 300 mg plus D 1500 mg [one dose] plus D 1500 mg once every 4 weeks [Q4W]; N=393) or D (1500 mg Q4W; N=389) vs S (400 mg twice daily; N=389). The European Organisation for Research and Treatment of Cancer (EORTC) 30-item Quality of Life (QoL) Questionnaire and the EORTC 18-item HCC QoL questionnaire were used to assess disease-related symptoms, physical functioning (PF), and Global Health Status (GHS)/QoL. Time to deterioration (TTD), defined as time from randomization to first clinically meaningful deterioration (worsening ≥10 points) confirmed at a subsequent visit or death, was assessed in pts with baseline scores ≤90 for symptoms or ≥10 for PF and GHS/QoL. Results: Across treatment arms, compliance rates for PROs were &gt;77% at baseline and &gt;70% overall. Baseline scores were comparable across treatment arms. TTD in fatigue, appetite loss, abdominal pain, PF, and GHS/QoL were significantly longer for both STRIDE and D vs S (Table). TTD in nausea and abdominal swelling were significantly longer for STRIDE vs S. Conclusions: The positive OS outcomes for STRIDE and D in pts receiving first-line treatment for uHCC in HIMALAYA were associated with clinically meaningful, pt-centered benefits, demonstrated by delayed worsening of disease-related symptoms, PF, and GHS/QoL vs S. Median TTD in months (95% CI) in PROs for STRIDE and D vs S. Clinical trial information: NCT03298451. [Table: see text]
Partition of respiratory mechanics in patients with acute respiratory distress syndrome and association with outcome: a multicentre clinical study
Authors: Lu Chen, Domenico L. Grieco, François Beloncle, Guang-Qiang Chen, Norberto Tiribelli, Fabiana Madotto, Sebastian Fredes, Cong Lu, Massimo Antonelli, Alain Mercat, Arthur S. Slutsky, Jian-Xin Zhou, Laurent Brochard
Journal: Intensive Care Medicine (2022)
Unique characteristics of lung-resident neutrophils are maintained by PGE2/PKA/Tgm2-mediated signaling
Authors: Geon Ho Bae, Ye Seon Kim, Ji Ye Park, Mingyu Lee, Sung Kyun Lee, Ji Cheol Kim, Jang Gyu Kim, Ye Ji Shin, Ho Lee, Soo-Youl Kim, Yong-Soo Bae, Brian A. Zabel, Hong Sook Kim, Yoe-Sik Bae
Journal: Blood (2022)